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Antimicrobial Agents and Chemotherapy, October 1998, p. 2564-2568, Vol. 42, No. 10
Stratton Veterans Affairs Medical Center and
Albany Medical College, Albany, New York 12208
Received 9 February 1998/Returned for modification 16 April
1998/Accepted 21 July 1998
One hundred ninety-five individual vancomycin-resistant
Enterococcus faecium (VRE) isolates from five
upstate New York hospitals were studied for antimicrobial
susceptibilities to LY333328, quinupristin-dalfopristin, teicoplanin,
ampicillin, and gentamicin. LY333328 was the most active antibiotic
against VRE. The effect of media and methods on the antibacterial
activity of LY333328, its synergy with ampicillin, and the
postantibiotic effects (PAE) of LY333328 and ampicillin were
evaluated. In microdilution tests, the MIC of LY333328 at which 90% of
the isolates were inhibited (MIC90) was 2 µg/ml in Mueller-Hinton II (MH II) broth and 1 µg/ml in brain heart
infusion (BHI) broth. In contrast, on MH II agar the MIC90
was 4 µg/ml and on BHI agar it was >16 µg/ml. Bactericidal
activity was observed for most strains at concentrations from 8 to
Gram-positive cocci, including
enterococci and staphylococci, have become common and
increasingly important pathogens in nosocomial infections (7, 14,
16, 18, 21, 29). Their increasing resistance to antibiotics
is well recognized (7, 16, 18, 32). Since its introduction
in 1959, vancomycin has been used widely in the treatment of infections
caused by gram-positive bacteria. This glycopeptide has been an
effective therapeutic agent against enterococci, but it has become less
effective since resistance to it was first recognized in the 1980s
(9, 10, 16, 21). The development of new glycopeptides,
including LY264826 and its semisynthetic derivative LY333328 (1,
2, 4, 9, 22, 33), is of special interest because of
the potential use of these drugs in the treatment of infections caused
by vancomycin-resistant enterococci, including vancomycin-resistant
Enterococcus faecium (VRE). The reasons for the
increased antimicrobial activity of these new glycopeptides, which
inhibit cell wall synthesis, include dimerization and the
increased stability of the drugs' interaction with peptidoglycan
(4). In addition, LY333328 is 100 times more effective than
vancomycin at inhibiting peptidoglycan transglycosylation in VRE
(1, 2).
LY333328 is a new semisynthetic N-alkylated glycopeptide antibiotic
with a molecular weight of 1,783 (free base), supplied as a phosphate
salt. Earlier reports suggest that the susceptibilities of enterococci
to LY333328 may depend on the choice of media and testing methods
(3, 13, 26, 27). This study describes our observations on
(i) the in vitro susceptibilities of VRE to LY333328 and five other
antibiotics on several bacteriologic media by three susceptibility
testing methods, (ii) the inhibitory and bactericidal effects of
LY333328, (iii) LY333328 synergy with three other antibiotics, and (iv)
the postantibiotic effects (PAE) of LY333328 in broth and in 50%
heat-inactivated human serum.
Antimicrobial agents.
LY333328 and vancomycin were
obtained from the Eli Lilly Research Laboratories (Indianapolis, Ind.),
quinupristin-dalfopristin (RP59500) was obtained from
Rhône-Poulenc Rorer (Collegeville, Pa.), teicoplanin was obtained
from Hoechst Marion Roussel Research Institute (Cincinnati, Ohio), and
ampicillin and gentamicin were obtained from the Sigma Chemical
Corporation (St. Louis, Mo.). For each drug, material from one lot
number was used throughout the study. Antibiotics were reconstituted
according to the manufacturers' directions, filtered through a sterile
0.45-µm-pore-size polysulfone membrane (Gelman Science, Ann Arbor,
Mich.), and used the same day.
Bacterial strains.
A total of 195 recent E. faecium isolates obtained from five upstate New York hospitals and
provided by the Wadsworth Laboratories, New York State Department of
Health, Albany, were included in this study. Conventional methods for
the identification and characterization of the isolates were employed
(12). The isolates had been typed by pulsed-field agarose
gel electrophoresis as part of another study. These typing data were
used to ensure that individual isolates were not duplicates of the same
strain. PCR analyses showed that 91% of the isolates contained the
vanA gene and 9% contained the vanB gene.
Susceptibility testing.
All susceptibility studies were
performed according to National Committee for Clinical Laboratory
Standards recommendations (23-25). Media were obtained from
BBL Microbiology Systems, Cockeysville, Md. For each medium, material
from one lot number was used throughout the study. Cation-adjusted
Mueller-Hinton II (MH II) media were used (MH II broth and MH II agar
provided 20 to 25 mg of Ca2+ and 10 to 12.5 mg of
Mg2+ per liter).
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparison of Inhibitory and Bactericidal Activities and
Postantibiotic Effects of LY333328 and Ampicillin Used Singly and in
Combination against Vancomycin-Resistant Enterococcus
faecium
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
133 times the MIC of the tube macrodilution in MH II broth. A
bactericidal effect of LY333328 plus ampicillin was demonstrated in
time-kill studies, but there was great strain-to-strain variability. By
the MH II agar dilution method, bacteristatic synergy (defined as a
fractional inhibitory concentration of <0.5) with LY333328 and
ampicillin was demonstrated for 61% of the strains tested. Under
similar conditions, there was synergy with LY333328 and
quinupristin-dalfopristin or gentamicin for 27 and 15% of the
strains tested, respectively. The PAE of LY333328 was
prolonged (23.0 h at 10 times the MIC). However, 50% normal pooled
human serum decreased the PAE to 12.2 h at 10 times the MIC. Test
conditions and media had a considerable effect on VRE susceptibilities
to LY333328. The prolonged PAE of LY333328, a potent new bactericidal
glycopeptide, and its synergy with ampicillin in a large
proportion of strains suggest that further evaluation of this drug in
pharmacokinetic studies and experimental infections, including those
with VRE, is warranted.
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
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Materials & Methods
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Discussion
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0.1% survival in the subculture.
Agar dilution studies were performed on MH II agar and BHI agar.
Inocula from overnight MH II agar cultures were transferred to MH II
broth and incubated until the turbidity reached 0.5 McFarland unit.
With a Steers replicator, bacterial inocula of 104 CFU were
placed in spots on antibiotic-containing MH II and BHI agar plates with
twofold increasing antibiotic concentrations. Following incubation for
24 h at 35°C in air, the MICs were read as the lowest antibiotic
concentrations at which one or no colonies were present. A faint haze
was disregarded.
The activities of LY333328-ampicillin combinations were evaluated in
96-well microdilution plates containing MH II broth. Combinations of
LY333328 and ampicillin, quinupristin-dalfopristin, or gentamicin were
evaluated on MH II agar by the methods described above. Bacteristatic
synergy was defined as a fractional inhibitory concentration of 0.5.
Time-kill assays were performed with the MICs determined by the tube
macrodilution method described above. Suspensions of bacteria in log
phase were used to inoculate flasks containing MH II broth and
antibiotics at 1, 2, 4, 10, 20, 30, and 40 times the MIC. The final
inoculum size was 105 CFU/ml. Flasks were incubated in a
shaking water bath at 35°C, and sampling was done at 0, 2, 6, 24, and
48 h. Samples (0.1 ml) were 10-fold serially diluted in 0.9%
NaCl, and 25-µl aliquots were plated in duplicate on MH II agar.
Undiluted 0.1-ml samples were also plated directly from the flasks,
providing a lower limit of detection of 101 CFU/ml. Plates
were incubated at 35°C, and colony counts were determined 24 h
later with an electronic colony counter (New Brunswick Scientific,
Edison, N.J.). Synergy was defined as a 2-log10-unit difference when two drugs were compared with the most effective single
drug and at least one of the drugs was present in a concentration that
did not affect the growth curve of the test organism when used alone.
Complete bactericidal activity was defined as the inability to recover
viable organisms in an undiluted sample and subsequent inability to
recover viable organisms from the same flask up to the final time
point. The potential antibiotic carryover for each assay was assessed
by plating concurrent samples from the highest drug concentrations and
controls at all dilutions. Aliquots were washed once in MH II broth to
remove antibiotic. No evidence of antibiotic carryover was found.
PAE.
The method of Craig and Gudmundsson was used to
determine PAE (11). Three or four colonies from an MH II
agar plate were used to inoculate MH II broth. The inoculated broth was
then serially diluted fivefold with MH II broth. All tubes were
incubated overnight at 37°C. Following incubation, the tube in each
set with an optical density at 580 nm closest to but not higher than
0.3 was selected as the inoculum. One milliliter of each inoculum was
then individually added to 9 ml of antibiotic-containing medium and a
drug-free control. The final inoculum size was 106 to
107 CFU/ml. After a 90-min incubation, the antibiotic was
removed from the bacterial suspension by centrifugation (1,200 × g) and washing in warm MH II broth. This procedure was
performed twice. Thereafter, sampling for PAE was done at 0, 1, 2, 3, 4, 5, 12, and 24 h by the same procedure as described for
kinetics-kill curves. The PAE (in hours) was determined by counts of
CFU per milliliter and the formula PAE = T 
C,
where T is the time required for a 1-log10-unit
increase in CFU per milliliter of the test culture after removal of the
antibiotic and C is the time required for a
1-log10-unit increase in CFU per milliliter for a similarly treated control. The PAE studies were performed in MH II broth and in
50% heat-inactivated pooled normal human serum (PNHS).
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RESULTS |
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Discussion
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Table 1 shows the MICs at which 50 and 90% of the isolates were inhibited (MIC50 and MIC90) and the range of MICs of LY333328, teicoplanin, vancomycin, quinupristin-dalfopristin, ampicillin, and gentamicin against 195 VRE strains tested by agar dilution on MH II agar. MIC90s of LY333328 and quinupristin-dalfopristin were in the susceptible range, while those of the other four antibiotics were in the highly resistant range. Table 2 shows the activities of LY333328, vancomycin, and teicoplanin against 189 of the same isolates, grouped into VanA and VanB phenotypes and tested in MH II broth. All VanA strains were highly resistant to vancomycin and were vanA positive by PCR. They were divided into two subgroups, VanA and VanA', based on their levels of resistance to teicoplanin. All VanB strains were resistant to vancomycin and susceptible to teicoplanin and were vanB positive by PCR. The microdilution method with MH II broth was used for the studies comparing VanA and VanB, because the methods and testing conditions can markedly influence the results of LY333328 susceptibility tests. The MIC90 of LY333328 decreased as susceptibilities to teicoplanin and vancomycin decreased. The highest MIC90 of LY333328 was for VanA strains highly resistant to teicoplanin (4 µg/ml). In contrast, the LY333328 MIC90 for VanA strains with intermediate resistance to teicoplanin was 2 µg/ml. The LY333328 MIC90 for VanB strains was still lower (1 µg/ml).
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The susceptibilities of 26 VRE strains to LY333328, quinupristin-dalfopristin, teicoplanin, ampicillin, vancomycin, and gentamicin were tested on MH II and BHI agars. The MIC90 of LY333328 was markedly higher on BHI agar than on MH II agar (>16 versus 4 µg/ml), while susceptibilities to the other antibiotics were similar on both agars.
The effects of BHI and MH II media on the susceptibilities of 26 VRE strains to LY333328 were also compared by the broth microdilution method. Results were the opposite of those obtained on agar media. Susceptibilities to LY333328 were lower in BHI broth than in MH II broth (MIC50, 0.5 versus 2 µg/ml; MIC90, 1 versus 2 µg/ml). In contrast, susceptibilities to vancomycin were essentially the same in both media. Agar dilution and microdilution tests comparing susceptibilities in MH II and BHI media were repeated two to four times. The results were highly reproducible.
In order to assess the importance of the method used for susceptibility testing, the susceptibilities of 14 VRE strains to LY333328 were determined in MH II medium with the micro- and macrodilution and agar dilution methods. The MIC90 varied from 0.25 µg/ml for macrodilution to 4 µg/ml for microdilution and agar dilution.
MICs, MBCs, and MBC/MIC ratios for LY333328 and ampicillin are shown in
Table 3. These studies were performed
with the macrodilution method in MH II broth. The MIC of LY333328
varied from 0.03 to 0.5 µg/ml, and that of ampicillin ranged from
16 to 512 µg/ml. The MBCs of LY333328 were from 8- to 133-fold
higher than the MICs.
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Bacteristatic synergy against VRE was observed for combinations of LY333328 and either ampicillin, quinupristin-dalfopristin, or gentamicin. In microdilution tests with MH II broth, there was synergy between LY333328 and ampicillin for 14 of 20 strains (70%). In tests with the MH II agar technique, the percentages of 33 strains for which synergy was observed for LY333328 and either ampicillin, quinupristin-dalfopristin, or gentamicin were 61, 27, and 15%, respectively.
Table 4 shows killing kinetics for
two of the five VRE strains tested following exposure to
increasing concentrations of LY333328 and ampicillin, used singly or in
combination. The effect of LY333328 on strain VRE-30 was rapid. Even at
zero time (
5 s, the time that elapsed between the start of the
experiment and the removal of the first sample), bactericidal activity
was seen, and by 6 h no surviving bacteria could be detected at 10 to 30 times the MIC. In contrast, with ampicillin no bactericidal
effect for this strain was observed at zero time, and some viable
organisms persisted at 48 h even at the highest drug concentration
tested. Combinations of LY333328 and ampicillin had complete
bactericidal activity at 2 h for 20 and 30 times the MIC and at
6 h for 10 times the MIC. Viable E. faecium
(strain VRE-30) organisms were detected at 48 h only at the lowest
drug concentrations studied (4 times the MIC for both drugs). A
beneficial drug interaction was seen at this and higher concentrations,
but true synergy was not demonstrated. Used alone, LY333328 inhibited
growth of strain VRE-31 at all concentrations tested (Table 4).
However, the number of viable organisms present at 48 h was
significantly lower than in the untreated control only at 40 times the
MIC. Ampicillin also inhibited growth at all concentrations, but in
contrast to LY333328, the number of surviving microorganisms present at
48 h was at least 5 log10 units lower at every
concentration tested than in the untreated control. Only the
combination of LY333328 and ampicillin having the highest drug
concentrations (40 times the MIC) had complete bactericidal activity
against this isolate, and that effect was seen only at 48 h. In
contrast, the combination of LY333328 and ampicillin at 30 times the
MIC eliminated all detectable viable organisms of strain VRE-30 within
2 h. Three additional VRE isolates were studied at drug
concentrations of 1 to 20 times the MIC, singly or in combination with
ampicillin. These studies showed up to a 1.5-log10-unit
drop in CFU per milliliter at 72 h (data not shown).
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The PAE of LY333328 and ampicillin at 10 times the MIC, used alone and in combination, were evaluated in MH II broth and in 50% PNHS. The PAE of LY333328 was clearly longer than that of ampicillin (18.7 h versus 4.0 h at 10 times the MIC). This PAE was extended to 23 h when the drugs were used in combination. PNHS decreased the PAE of LY333328 by 30%, while no change was observed for the PAE of ampicillin. For combinations of LY333328 and ampicillin evaluated with 50% PNHS, the PAE decreased by 30 to 50%.
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DISCUSSION |
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This study clearly demonstrates that the susceptibilities of VRE to LY333328 are both medium and method dependent. In comparative studies using the microdilution method in MH II broth (cation adjusted), the MIC90 of LY333328 was 2 µg/ml, while in BHI broth the MIC90 was 1 µg/ml. Tested by macrodilution in MH II broth, the MIC90 was only 0.25 µg/ml. In agar dilution studies, the MIC90 on MH II agar was 4 µg/ml while on BHI agar it was >16 µg/ml. Nicas et al. noted in earlier studies with two other semisynthetic glycopeptides the importance of medium and method selection in evaluation of antimicrobial activities against E. faecium (26, 27). Higher MIC90s than those obtained in this study (8 versus 2 µg/ml) have previously been reported by Biavasco et al. for LY333328 tested in MH II broth (BBL) by microdilution (5). Schwalbe et al. obtained an MIC90 of 1 µg/ml by microdilution, but information on medium type was not provided (30). On Iso-Sensitest agar (Unipath Ltd., Basingstoke, United Kingdom), the MIC90 was 0.25 µg/ml for VanA phenotypes and 0.12 µg/ml for VanB strains (13). Jones et al. found the MIC90 for E. faecium strains in cation-adjusted MH broth (Difco) to be 4 µg/ml (17). The reasons for these variations in reported susceptibilities are not clear, but the importance of different medium cation concentrations has been noted previously in reports evaluating antimicrobial susceptibilities of Pseudomonas aeruginosa to aminoglycosides and imipenem (8, 19). It has been noted that susceptibility results for vancomycin may depend on the media used, the method employed, and the physicochemical characteristics of the drug, independent of the growth rate of the microorganism (15).
We found LY333328 to be bactericidal when evaluated by
macrodilution subcultures in time-kill analyses. This activity
was dependent upon drug concentration and was enhanced by
ampicillin (Table 4). However, true synergy between LY333328 and
ampicillin was not demonstrated. The inability to demonstrate synergy
may be due to the very rapid killing of susceptible VRE at the drug concentrations tested. In our studies, LY333328 was bactericidal only
at concentrations 8 to 133 times the MIC. However, bactericidal activity was demonstrated at 4 to 8 or 2 to 64 times the MIC in two
other studies (5, 30). While Biavasco et al. (5)
found that a 2-log10-unit decrease in CFU per
milliliter required an LY333328 concentration of 8 times the MIC and a
3-log10-unit decrease required 16 times the MIC in kill
curves, for three of five strains we demonstrated that concentrations
of LY333328 as high as 20 times the MIC caused only a
1.5-log10-unit drop in CFU per milliliter. However,
bactericidal activity of LY333328 against two additional strains at 20 to 40 times the MIC was observed. The differences in these observations
may be strain related.
In a multiple-dose in vitro pharmacodynamic model, Zelenitsky et al. demonstrated synergy of LY333328 with gentamicin and rapid bactericidal action (34). Our MH II broth microdilution data demonstrated bacteristatic synergy of LY333328 with ampicillin in 70% of the strains tested. Furthermore, bacteristatic synergy with ampicillin, quinupristin-dalfopristin, or gentamicin was observed in tests with MH II agar (for 61, 27, and 15%, respectively, of the strains tested).
Our data indicate that the PAE for LY333328 is prolonged (18.7 h at 10 times the MIC). Furthermore, the presence of ampicillin (10 times the MIC) increased the PAE to 23 h. However, 50% serum decreased the PAE by 30 to 50%. These data indicate the persistence of the effect of LY333328 for many hours and therefore the possibility that therapy may require infrequent dosing. Although their method was different than ours, Novelli et al. (28) also demonstrated a prolonged PAE for LY333328 (at 8 times the MIC the PAE was 7.4 ± 2.2 h).
Pharmacokinetic studies in rats have shown that the half-life for LY333328 is 9.7 h, that 77% of the drug is bound to protein, and that there is no evidence of drug accumulation in plasma but that there is evidence for deep compartmentalization (20). LY333328 has been shown to be effective in the treatment of mice with renal infection and in leukopenic mice bacteremic with VRE (6, 31).
In summary, of the drugs evaluated in this study, LY333328 is the most active, and it can be rapidly bactericidal against VRE. The susceptibilities to LY333328 vary with media and study methods. The PAE is prolonged. Bacteristatic synergy with LY333328 was observed with ampicillin, quinupristin-dalfopristin, and gentamicin. Further evaluation of this new semisynthetic glycopeptide against VRE is highly recommended.
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ACKNOWLEDGMENTS |
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This study was supported by the Eli Lilly Laboratories and in part by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.
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FOOTNOTES |
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* Corresponding author. Mailing address: Infectious Disease Section, 111D, Stratton VA Medical Center, 113 Holland Ave., Albany, NY 12208. Phone: (518) 462-3311, ext. 3080. Fax: (518) 462-3350. E-mail: BALTCH.ALDONA{at}Albany.va.gov.
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Materials & Methods
Results
Discussion
References
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